A report from the House of Commons Public Accounts Committee concludes that information is routinely withheld from doctors and researchers about the methods and results of clinical trials on treatments currently prescribed in the United Kingdom (1). Invariably the bodies responsible for the approval of new drugs only have access to the results of studies which present the drug under investigation in a positive light which those which do not as well as those which show no benefit or even undesirable effects may never be revealed. Essentially this means that the regulatory authorities do not have the total picture which is needed if sound decisions regarding approval for usage are to be made. Although this problem has been recognised for many years there has been a failure on the part of government, industry and the professional bodies to take the necessary action to deal with it. It was recommended that the full methods and results are available to doctors and researchers for all trials on all uses of all treatments currently being prescribed.
The report considered what happened with Tamiflu, which had been stockpiled between 2006-07 and 2012-13, on the basis that it would be needed in the event of a pandemic of influenza. During this time the Department of Health spent £560 on antiviral medicines, of which £424 was for Tamiflu and £136 for Relenza. Valuable insight into the background to this policy can be gained from some of the evidence presented to the Committee by Ben Goldacre author of “Bad Pharma” and Fiona Godlee, editor-in-chief of the British Medical Journal.
With respect to Tamiflu, Fiona referred to the work of a team at the Cochrane Commission led by Tom Jefferson who discovered that there had been about 123 trials conducted on Tamiflu and that the pharmaceutical company Roche was aware of 74 completed trials. Of those, it appears that the European Medicines Agency (EMA) had access to only 15 incomplete accounts. In the UK, the National Institute for Health and Care Excellence (NICE) had received 4incomplete accounts of trials.
She described those involved in Cochrane Commission reviews as
“slightly obsessive and very scientifically determined people”
While it might be expected that the regulatory bodies would require all the evidence to be provided for evaluation in practice according to Fiona they do not ask for it even though they are entitled to have it. Because they are under-resourced and stretched they tend to take the manufacturer’s word for it. By contrast, in Germany, manufacturers have a legal obligation to provide the Institute for Quality and Efficiency in Healthcare (IQWIG), which performs a similar role to NICE, with a full list of clinical trials and supporting clinical study reports.
In a letter to the Chair of NICE, Sir Michael Rawlins, Fiona described the response from IQWIG when it discovered that had not been provided with all the relevant data on reboxitine, a drug produced by Pfizer(2). The company was told it would only approve the drug for reimbursement if all the results were made available to the Institute. The full dataset showed that the drug was ineffective and possibly harmful. This illustrates very effectively how the regulatory bodies can actually be misled and in reality manipulated by the drug companies.
The report implied that those responsible for the expenditure involved in stockpiling the Tamiflu did not have the evidence which clearly demonstrated the efficacy of the drug, especially in the light of the Cochrane report cited above. Hence it is particularly relevant that when the Chief Medical Officer, Dame Sally Davies, was presenting evidence to the Committee she attempted to cast doubts on the credibility of the Cochrane conclusions. In particular she claimed that the Cochrane group
“extracted data from 25 studies but excluded 43 and took no data from published studies.”
The reply to this comment included the following points:
• Not all the trials on conducted on Tamiflu, produced by Roche had been published in the scientific literature
• Not all of those published have been totally accurate. The original results are contained in “Clinical Study Reports” which are extremely detailed and comprehensive. The experience of the Cochrane group has provided examples of discrepancies between the information in these Clinical reports and what appeared in the scientific paper. The group cited 2 examples which stated that:
“there were no drug related serious adverse events”
and
“No serious adverse events were noted in the major trials and no significant changes were noted in laboratory parameters”
However, the equivalent clinical study reports for these two trials describe 10 serious adverse events (in nine participants), some of which were classified as “possibly” related to Tamiflu. They also discovered many of the authors of the scientific papers had not actually seen the raw data. At least one paper had been ghost written.
As a consequence the team decided that there were serious doubts about the reliability of the scientific papers from Roche and that they should restrict their analyses to the original Clinical Study Reports, a strategy which seems entirely reasonable
• There was one study, which was the largest treatment trial of Tamiflu, where the only published information was a 300-word abstract of a conference presentation. The author, Professor Treanor did not participate in the original study and admitted on Channel 4 News that he could not even remember presenting it at a conference in 2000
• Hence it was not correct for Dame Sally to conclude that 42 studies had been excluded. The position was that for 42 studies it was possible to obtain sufficient information to determine their suitability for further assessment and analysis in the review… a very different context
The work of the Cochrane team was fraught with difficulties and in some cases the information was only released in response to Freedom of Information requests and even then there was great reluctance to provide it. The claims of the regulators that they had all the information needed to make sound decisions just do not stand up to rigorous examination.
There is absolutely no reason to doubt the Cochrane conclusion its review has had access to the most extensive data set ever used in these particular drug types and therefore provides a transparent assessment. Consequently it has not been possible to draw conclusions about its effect on complications or transmission. Accepting that it is incomplete at this stage, it is certainly the best that has been produced so far and must carry mush more weight than anything from the regulators who have not had access to such comprehensive evidence.
The Government and the officials in the Department of Health would do well to take note of the Public Accounts Committee Report.
REFERENCES
1. http://www.publications.parliament.uk/pa/cm201314/cmselect/cmpubacc/295/295.pdf
2. http://www.bmj.com/tamiflu/nice